The present invention relates to compounds that have the property of reducing serum glucose and serum triglyceride levels in diabetic mammals without the undesirable property of reducing serum thyroxine levels. More particularly, the present invention relates to 3,5-di-iso-propyl-heptatrienoic acid derivatives having the above-noted biological property.
Compounds that have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. It is now general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors are respectively designated the RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RARxcex1, RARxcex2 and RARxcex3, in RXR the subtypes are: RXRxcex1, RXRxcex2 and RXRxcex3. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids are mediated by one or more of the RAR receptor subtypes. Accordingly, among compounds having agonist-like activity at retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property.
For a general overview of the retinoid receptors see Mangelsdorf et al. (1994) The Retinoid Receptors In: The Retinoids, edited by Sporn et al. p 319-349. Raven Press, Ltd., New York. For another general overview see Dawson and William H. Okamura, Chemistry and Biology of Synthetic Retinoids, published by CRC Press Inc., 1990, pages 324-356. The following further patents are of interest as background to the present invention: U.S. Pat. Nos. 5,721,103; 5,801,253; 6,326,397; PCT Publications WO 97/12853 and WO 01/19770.
Relatively recently it has become known that certain retinoid compounds are capable of reducing serum glucose levels in diabetic mammals. Mukheijee, R.; Davies, P. J.; Crombie, D. L. Bishoff, E. D.; Cesario, R. M.; Jow Hamann, L. G.; Boehm, M. F.; Mondon, C. E.; Nadzan, A. M.; Paterniti, J. R. Jr.; Heyman, R. A. Sensitization of Diabetic and Obese Mice to Insulin by Retinoid X Receptor Agonists. Nature 1997, 386 (6623), 407-410. The compound (2E, 4E, 1xe2x80x2S, 2xe2x80x2S)-3-methyl-5-[2xe2x80x2-methyl-2xe2x80x2-(5, 5,8,8-tetramethyl-5,6, 7,8-tetrahydro-naphthalen-2-yl)-cyclopropyl]-penta-2,4-dienoic acid, described in U.S. Pat. No. 6,114,533 has this property. A disadvantage of the prior art retinoid compounds that reduce serum glucose levels is that their administration usually also results in the pharmacologically undesirable reduction of seruim thyroxine levels and in a transient increase in serum triglyceride levels. The present invention is directed to novel compounds that do not have these undesirable side effects.
The present invention relates to compounds of Formula 1 
where R1 is alkyl of 1 to 3 carbons;
R2 is independently H or F;
R3 is propyl or iso-propyl, and
R4 is is H, alkyl of 1 to 6 carbons, CH2OR5 or CH2OCOR5 where R5 is alkyl of 1 to 3 carbons, or a pharmaceutically acceptable salt of said compound.
The present invention also relates to pharmaceutical compositions incorporating the compounds of Formula 1 and to methods of treatment of diabetic mammals with pharmaceutical compositions containing one or more compounds of Formula 1 to reduce serum glucose levels in said mammals. The present invention also relates to the methods of using the compounds of the invention to treat diseases and conditions that are responsive to treatment by retinoids.
The term alkyl refers to and covers any and all groups which are known as normal alkyl and branched-chain alkyl.
A pharmaceutically acceptable salt may be prepared for any compound in this invention having a functionality capable of forming a salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules.
The compounds of the present invention include olephinic double bonds about which trans and cis (E and Z) stereoisomerism can exist. The compounds of the present invention have the specific orientations of substituents relative to the double bonds as is indicated in the name of the respective compound, and/or by specific showing in the structural formula of the orientation of the substituents relative to the respective double bonds.
Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. The scope of the present invention is intended to cover the trans and cis (E and Z) isomers as specifically shown and/or named, as well as pure enantiomers (optical isomers), diastereomers, mixtures of diastereomers and racemic mixtures of enantiomers.
Reaction Scheme 1 discloses a presently preferred synthetic route to compounds of the invention. Although this synthetic route is general, the cis and/or trans isomerism of the compounds of the invention is indicated properly in the formulas. 
Referring now to Reaction Scheme 1, the starting material is 2,4-diisopropyl-phenol (Intermediate 1 that can be obtained from 3,5-diisopropylsalicylic acid, as is shown in Reaction Scheme 3 below) is brominated in acetic acid as a solvent to yield 2-bromo4,6-diisopropyl-phenol (Intermediate 2).
Bromo-4,6-diisopropyl-phenol is then reacted with a reagent of the formula R3X1 in the presence of base, to give 1-bromo-3,5-diisopropyl-2-alkyloxy-benzene (Formula 2). The variable R3 is defined as in connection with Formula 1 and X1 is a leaving group. In the synthesis of the presently preferred compounds of the invention R3X1 is propyl iodide. The compound of Formula 2 is then reacted with tri-iso-propylborate in the presence of strong base, such as butyl lithium, at cold temperature to provide 2-alkoxy-3,5-diisopropyl-phenylboronic acid (Formula 3). The boronic acid derivative (Formula 3) is reacted with a 3-iodo-pent-en-1-ol derivative (Reagent 4) in the presence tetrakis(triphenylphosphine)palladium (0) catalyst and base (such as sodium carbonate) to provide a 3-(3,5-diisopropyl-2-alkoxy-phenyl)-pent-2-en-1-ol derivative (Formula 5). The variables R1 and R2 of Reagent 4 are defined as in connection with Formula 1. 3-Iodo-pent-2-en-1-ol (available from Synthesis, 1995, 47-55.) serves as an example and is utilized in the synthesis of a preferred compound of the invention. Other reagents within the scope of the formula of Reagent 4 are either available commercially, or from the chemical literature, or can be synthesized by one of ordinary skill in the art by apparent modifications of known literature procedures.
The 3-(3,5-diisopropyl-2-alkoxy-phenyl)-pent-2-en-1-ol derivative (Formula 5) is subjected to oxidation with N-methylmorpholine-N-oxide (NMO) in the presence of catalytic amounts of tetrapropylammonium peruthenate (TPAP) to give a 3-(3,5-diisopropyl-2-alkoxy-phenyl)-pent-2-enal derivative (Formula 6). The aldehyde of Formula 6 is subjected to a Horner Emmons reaction with Reagent 7 where the variable R2 is defined as in connection with Formula 1. The Horner Emmons reaction per se is well known in the art, and is conducted in an aprotic solvent, such as heptane or tetrahydrofuran (THF) or mixtures of aprotic solvents, in the presence of strong base, such an n-butyl lithium or lithium diisopropylamide (LDA). 4-diethoxy-phosphoryl)-3-methyl-but-2-enoic acid ethyl ester (R2=H, available from JOC, 1974, 39, 821) and the corresponding 2-fluoro derivative serve as examples for Reagent 7. The product of the Horner Emmons reaction is a 7-(3,5-diisopropyl-2-alkoxy-phenyl)-3-methyl-nona-2,4,6-trienoic acid ethyl ester derivative of Formula 8 which is a compound of the invention, within the scope of Formula 1. Saponification of the ester compound of Formula 8 provides the free acid compounds of the invention (or pharmaceutically acceptable salts thereof) as shown by Formula 9.
Referring now to Formula 1, in the presently preferred compounds of the invention the R1 group is methyl or ethyl, R2 is H and R3 is propyl. R4 is preferably hydrogen, or alkyl of 1 to 3 carbons, or a pharmaceutically acceptable salt of the carboxylic acid compound.
The synthesis of the presently most preferred compounds of the invention is shown in Reaction Schemes 2 and 3 and a detailed description of the experimental procedures for synthesizing these most preferred exemplary compounds is also provided below. Reaction Scheme 2 follows the general synthetic route of Reaction Scheme 1 whereas Reaction Scheme 3 discloses a synthetic route which is presently preferred for the synthesis of Compound 16. 
2-Bromo-4,6-diisopropyl-phenol (Intermediate 2)
To a solution of 2,4-diisopropyl-phenol (Intermediate 1, 10.0 g, 56 mmol) in acetic acid (20 mL) was added bromine (3.5 mL, 67 mmol) at 0xc2x0 C. The mixture was stirred at 0xc2x0 C. for 15 min, quenched with water and extracted with EtOAc. The organic layer was washed successively with NaOH (4M, 85 mL), NaHSO3, and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexanes) to yield the title compound as a light yellow oil (14.5 g, 100%).
1H NMR (300 MHz, CDCl3): xcex4 1.21 (d, J=7.0 Hz, 6H), 1.24 (d, J=7.0 Hz, 6H), 2.81 (hept, J=7.0 Hz, 1H), 3.29 (hept, J=7.0 Hz, M1), 5.41 (s, 1H), 6.98 (d, J=2.1 Hz, 1H), 7.15 (d, J=2.1 Hz, 1H).
1-Bromo-3,5-diisopropyl-2-propoxy-benzene (Intermediate 3)
A mixture of 2-bromo-4,6-diisopropyl-phenol (Intermediate 2, 14.5 g, 56 mmol), 1-iodopropane (16.5 mL, 169 mmol), and K2CO3 (38.6 g, 280 mmol) in acetone (100 mL) was stirred at room temperature for 64 h. The solvent was removed in vacuo, and the residue was taken up in CHCl3 and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash column chromatography on silica gel (hexanes) to yield the title compound as a colorless oil (16.0 g, 95%).
1H NMR (300 MHz, CDCl3): xcex4 1.08 (t, J=7.5 Hz, 3H), 1.22 (2d, J=7.0 Hz, 12H), 1.86 (m, 2H), 2.83 (hept, J=7.0 Hz, 1H), 3.32 (hept, J=7.0 Hz, 1H), 3.83 (t, J=6.6 Hz, 2H), 7.02 (d, J=2.1 Hz, 1H), 7.22 (d, J=2.3 Hz, 1H).
2-Propoxy-3,5-diisopropyl-phenylboronic acid (Intermediate 4)
To a solution of n-BuLi (1.6 M in hexane, 40 mL, 64.2 mmol) in THF (150 mL) at xe2x88x9278xc2x0 C. was added 1-bromo-3,5-diisopropyl-2-propoxy-benzene (Intermediate 3,16.0 g, 53.5 mmol) in THF (50 mL and 10 mL rinse) slowly. Thereafter 0.5 h triisopropyl borate (24.7 mL, 107 mmol) in THF (40 mL) was added slowly and the reaction was stirred at xe2x88x9278xc2x0 C. for 1 h and at room temperature for 2 h. The reaction was then treated with 3M HCl (200 mL) at room temperature for 1.5 h, and extracted with EtOAc (xc3x972). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was washed with hexane to give 3.28 g of the title compound as a white solid. The hexane solution was filtered through a pad of SiO2 to give additional 11.0 g of the title compound as a yellow slurry containing minor impurities. This crude material was used in the next step without flirter purification.
1H NMR (300 MHz, CDCl3): xcex4 1.07 (t, J=7.5 Hz, 3H), 1.24 (d, J=6.7 Hz, 6H), 1.25 (d, J=6.7 Hz, 6H), 1.86 (m, 2), 2.89 (hept, J=7.0 Hz, 1H), 3.26 (hept, J=7.0 Hz, 1H), 3.76 (t, J=6.7 Hz, 2H), 5.91 (br s, 2H), 7.24 (d, J=2.6 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H).
3-(3,5-Diisopropyl-2-propoxy-phenyl)-pent-2-en-1-ol (Intermediate 5)
A mixture of 2-propoxy-3,5-diisopropyl-phenylboronic acid (Intermediate 4, 3.28 g, 12.4 mmol), 3-iodo-pent-2-en-1-ol (3.95 g, 18.6 mmol), Pd(PPh3)4 (720 mg, 0.62 mmol), and Na2CO3 (2M, 31 mL, 62 mmol) in toluene (40 mL) and EtOH (30 mL) was heated to 92xc2x0 C. for overnight. The reaction was cooled to room temperature and extracted with EtOAc (xc3x973). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The additional 1.10 g of Intermediate 4 as described above was subjected to the same reaction conditions to also give crude product. The combined crude products were purified by flash column chromatography on silica gel (10% EtOAc-hexanes) to yield the title compound as a light brown oil (9.2 g, 56% over 2 steps).
1H NMR(300MHz, CDCl3): xcex4 0.99 (t, J=7.3 Hz, 3H), 1.11 (t, J=7.5 Hz, 3H), 1.23 (2d, J=6.7 Hz, 12H), 1.73 (m, 2H), 2.43 (br q, J=7.3 Hz, 2H), 2.84 (hept, J=6.7 Hz, 1H), 3.31 (hept, J=7.0 Hz, 1H), 3.62 (br s, 1H), 5.79 (br t, J=7.5 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H).
3-(3,5-Diisopropyl-2-propoxy-phenyl)-pent-2-enal(Intermediate 6)
To a solution of 3-(3,5-diisopropyl-2-propoxy-phenyl)-pent-2-en-1-ol (Intermediate 5, 9.2 g, 30.3 mmol) and NMO (10.6 g, 90.8 mmol) in CH2Cl2 (50 mL) at 0xc2x0 C. was added catalytic amount of TPAP. The reaction was stirred at room temperature for 1.5 h, and then loaded directly onto a short pad of silica gel. Elution with 5% EtOAc-hexanes yielded the title compound as a brown oil (8.77 g, 95%).
1H NMR (300 MHz, CDCl3): xcex4 0.96 (t, J=7.5 Hz, 3H), 1.11 (t, J=7.3 Hz, 3H), 1.23 (2d, J=6.7 Hz, 12H), 1.68 (m, 2H), 2.65 (m, 2H), 2.86 (hept, J=6.9 Hz, 1H), 3.31 (hept, J=6.9 Hz, 1H), 3.59(t, J=6.5 Hz, 2H), 6.11 (dt, J=8.2, 1.5 Hz, 1H), 6.77 (d, J=2.3 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 9.48 (d, J=8.2 Hz, 1H).
7-(3,5-Diisopropyl-2-propoxy-phenyl)-3-methyl-nona-2, 4,6-trienoic acid ethyl ester (Compound 7)
To a solution of 4-(diethoxy-phosphoryl)-3-methyl-but-2-enoic acid ethyl ester (10.6 mL, 43.6 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 20 mL) and THF (80 mL) at xe2x88x9278xc2x0 C. was added n-BuLi dropwise (1.6 M in hexanes, 27.2 mL, 43.6 mmol). After 10 min, 3-(3,5-diisopropyl-2-propoxy-phenyl)-pent-2-enal (Intermediate 6, 8.77 g, 29.0 mmol) in THF (15 mL and 5 mL rinse) was added slowly to the reaction. The mixture was stirred at xe2x88x9278xc2x0 C. for 2h, was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was separated, washed successively with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2.5% EtOAc-hexanes) to yield the title compound as a yellow syrup (11.4 g, 95%).
1H NMR (300 MHz, CDCl3): xcex4 0.95 (t, J=7.5 Hz, 3H), 1.03 (t, J=7.5 Hz, 3H), 1.22 (2d, J=6.7 Hz, 12H), 1.27 (t, J=7.2 Hz, 3H), 1.66 (m, 21), 2.13 (d, J=1.2 Hz, 3H), 2.56 (br q, J=7.3 Hz, 2H), 2.85 (hept, J=6.9 Hz, 1H), 3.33 (hept, J=6.9 Hz, 1H), 3.68 (m, 2H), 4.15 (q, J=7.2 Hz, 2H), 5.73 (s, 1H), 6.22 (d, J=10.9 Hz, 1H), 6.24 (d, J=15.3 Hz, 1H), 6.59 (dd, J=15.1, 11.0 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H).
7-(3,5-Diisopropyl-2-propoxy-phenyl)-3-methyl-nona-2,4,6-trienoic acid (Compound 8)
A solution of 7-(3,5-diisopropyl-2-propoxy-phenyl)-3-methyl-nona-2,4,6-trienoic acid ethyl ester (Compound 7, 11.4 g, 27.7 mmol) in EtOH (220 mL) was treated with 1M NaOH (111 mL, 111 mmol) and was heated to 80 xc2x0 C. for 3 h. The mixture was cooled to room temperature, acidified with 1M HCl (115 mL), and was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by recrystallization from CH3CN to yield the title compound as an off-white solid (7.56 g, 71%).
1H NMR (300 MHz, CDCl3): xcex4 0.95 (t, J=7.3 Hz, 3H), 1.03 (t, J=7.5 Hz, 3H), 1.23 (2d, J=7.0 Hz, 12H), 1.66 (m, 2H), 2.14 (d, J=0.9 Hz, 3H), 2.57 (br q, J=7.6 Hz, 2H), 2.85 (hept, J=6.7 Hz, 1H), 3.33 (hept, J=6.7 Hz, 1H), 3.58 (m, 2H), 5.76 (s, 1H), 6.23 (d, J=10.9 Hz, 1H), 6.27 (d, J=15.0 Hz, 1H), 6.63 (dd, J=15.1, 11.0 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H).
2,4-Diisopropyl-phenol (Intermediate 1)
A mixture of 3,5-diisopropylsalicylic acid (Intermediate 9, 25 g, 0.11 mol, available from Aldrich) and quinoline (50 mL) was refluxed for 4 h. The mixture was cooled to room temperature, diluted with EtOAc (200 mL), washed with 1M HCl (2xc3x97200 mL) until acidic, then with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% then 10% EtOAc-hexanes) to yield the title compound as a yellow oil (20 g, xcx9c100%).
1H NMR (300 MHz, CDCl3): xe2x96xa1 1.23 (d, J=6.7 Hz, 6H), 1.27 (d, J=6.7 Hz, 6H), 2.84 (m, 1H), 3.19 (m, 1H), 4.55 (br d, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.83 (dd, J=8.2, 2.3 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H).
6,8-Diisopropyl-4-methyl-chromen-2-one (Intermediate 11)
A mixture of 2,4-diisopropyl-phenol (Intermediate 1, 2.2 g, 12.4 mmol) and ethyl acetoacetate (4.0 mL, 30.9 mmol) was treated with 75% H2SO4 (12 mL, pre-mixed and cooled to 0xc2x0 C.). The mixture was stirred at room temperature for 16 h, poured onto ice and extracted with EtOAc. The organic layer was separated, washed successively with saturated NaHCO3, H2O, and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% EtOAc-hexanes) to yield the tide compound as a light yellow syrup (2.6 g, 87%).
1H NMR (300 MHz, CDCl3): xe2x96xa1 1.29 (d, J=7.0 Hz, 6H), 1.30 (d, J=7.0 Hz, 6H), 2.45 (d, J=1.2 Hz, 3H), 2.98 (m, 1H), 3.63 (m, 1H), 6.28 (d, J=1.2 Hz, 1H), 7.34 (d,J=2.1 Hz, 1H).
2-(3-Hydroxy-1-methyl-propenyl)-4,6-diisopropyl-phenol (Intermediate 12)
To a solution of 6,8-diisopropyl-4-methylchromen-2-one Intermediate 11, 2.6 g, 10.7 mmol) in Et2O (100 mL) at 0xc2x0 C. was added LiAlH4 portionwise (405 mg, 10.7 mmol). The reaction was stirred at 0xc2x0 C. for 1 h, quenched by careful addition of ice, and acidified with 1M HCl. The mixture was then extracted with EtOAc. The organic layer was separated, washed successively with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (20% EtOAc-hexanes) to yield the title compound as a nearly colorless syrup (1.82 g, 70%).
1H NMR (300 MHz, CDCl3): xe2x96xa1 1.22 (d, J=7.0 Hz, 6H), 1.25 (d, J=7.0 Hz, 6H), 2.06 (d, J=0.6 Hz, 3H), 2.83 (m, 1H), 3.28 (m, 1H), 3.94 (d, J=7.3 Hz, 2H), 5.96 (td, J=7.0, 1.5 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 6.98 (d, J=2.1 Hz, 1H).
3-(3.5-Diisopropyl-2-propoxy-phenyl)-but-2-en-1-ol (Intermediate 13)
To a solution of 2-(3-hydroxy-1-methyl-propenyl)-4,6-diisopropyl-phenol (Intermediate 12, 1.82 g, 7.3 mmol) and 1-iodopropane (0.79 mL, 8.1 mmol) in DMF (20 mL) at room temperature was added CsF (3.9 g, 25.6 mmol). The reaction was stirred at room temperature for 1.5 h, diluted with EtOAc, washed successively with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% EtOAc-hexanes) to yield the title compound as an off-white solid (2.06 g, 97%).
1H NMR (300 MHz, CDCl3): xe2x96xa1 1.01 (t, J=7.3 Hz, 3H), 1.23 (d, J=6.7 Hz, 12H), 1.74 (m, 2H), 2.11 (d, J=0.9 Hz, 3H), 2.85 (m, 1H), 3.31 (m, 1H), 3.64 (t, J=6.7 Hz, 2H), 3.81 (d, J=7.6 Hz, 2H), 5.84 (td, J=7.3, 1.5 Hz, 1H), 6.75 (d, J=2.1 Hz, 1H),7.01 (d,J=2.4 Hz, 1H).
3-(3,5-Diisopropyl-2-propoxy-phenyl-but-2-enal (Intermediate 14)
To a solution of 3-(3,5-diisopropyl-2-propoxy-phenyl)-but-2-en-1-ol (Intermediate 13, 2.06 g, 7.1 mmol) and NMO (2.5 g, 21.3 mmol) in CH2Cl2 (10 mL) at 0xc2x0 C. was added catalytic amount of TPAP. The reaction was stirred at room temperature for 45 min and then loaded directly onto a short pad of silica gel. Elution with 10% EtOAc-hexanes yielded the title compound as a yellow syrup (2.1 g, 100%).
1H NMR (300 MHz, CDCl3): xe2x96xa1 0.96 (t, J=7.3 Hz, 3H), 1.22 (d, J=7.0 Hz, 12H), 1.69 (m, 2H), 2.33 (d, J=1.2 Hz, 3H), 2.85 (m, 1H), 3.31 (m, 1H), 3.60 (t, J=6.5 Hz, 2H), 6.10 (dq, J=8.2, 1.5 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 9.43 (d, J=8.2 Hz, 1H).
7-3,5-Diisopropyl-2-propoxy-phenyl)-3-methyl-octa-2,4,6-trienoic acid ethyl ester (Compound 15)
To a solution of 4-(diethoxy-phosphoryl)-3-methyl-but-2-enoic acid ethyl ester (3.4 mL, 14.2 mmol, in DMPU (16 mL) and THF (32 mL) at xe2x88x9278xc2x0 C. was added n-BuLi dropwise (1.6 M in hexanes, 8.9 mL, 14.2 mmol). After 10 min, 3-(3,5-diisopropyl-2-propoxy-phenyl)-but-2-enal (Intermediate 14, 2.1 g, 7.1 mmol) in THF (8 mL) was added slowly to the reaction. The mixture was stirred at xe2x88x9278xc2x0 C. for 1 h, and was quenched with saturated NH4Cl, extracted with EtOAc.
The organic layer was separated, washed successively with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (4% EtOAc-hexanes) to yield the title compound as a yellow syrup (2.45 g, 87%).
1H NMR (300 MHz, CDCl3): xe2x96xa1 0.95 (t, J=7.3 Hz, 3H), 1.22 (d, J=6.7 Hz, 6H), 1.23 (d, J=7.0 Hz, 3H), 1.27 (d, J=7.0 Hz, 3H), 1.66 (m, 2H), 2.13 (d, J=1.2 Hz, 3H), 2.19 (br s, 3H), 2.84 (m, 1H), 3.32 (m, 1H), 3.58 (t, J=6.2 Hz, 2H), 4.14 (q, J=7.3 Hz, 2H), 5.72 (s, 1H), 6.20 (d, J=15.5 Hz, 1H), 6.21 (d, J=10.6 Hz, 1H), 6.56 (dd, J=15.8, 10.3 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 7.02 (d, J=2.3 Hz, H1).
7-(3,5-Diisopropyl-2-propoxy-phenyl)-3-methyl-octa-2,4,6-trienoic acid (Compound 16)
A solution of 7-(3,5-diisopropyl-2-propoxy-phenyl)-3-methyl-octa-2, 4,6-trienoic acid ethyl ester (Compound 15, 2.45 g, 6.16 mmol) in EtOH (50 mL) was treated with 1M NaOH (25 mL, 25 mmol) and was heated to 80xc2x0 C. for 4 h. The mixture was cooled to room temperature, acidified with 1M HCl, and was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by recrystallization from CH3CN to yield the title compound as a white solid (1.87 g, 82%).
1H NMR (300 MHz, CDCl3): xe2x96xa1 0.95 (t, J=7.3 Hz, 3H), 1.22 (d, J=6.7 Hz, 6H), 1.23 (d, J=7.0 Hz, 6H), 1.66 (m, 2H), 2.13 (d, J=1.2 Hz, 3H),2.20 (br s, 3H), 2.85 (m, 1H), 3.32 (m, 1H), 3.58 (t, J=6.2 Hz, 2H), 5.75 (s, 1H), 6.22 (d, J=10.9 Hz, 1H), 6.23 (d, J=15.3 Hz, 1H), 6.61 (dd, J=15.3, 10.8 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H).
It has been discovered in accordance with the present invention that compounds of this invention are capable of significantly reducing serum glucose levels and reducing or maintaining serum triglyceride levels in diabetic mammals, without the undesirable side effects of reducing serum thyroxine levels (hypothyroidism) and transiently raising triglyceride levels (hypertriglyceridemia). The compounds of the invention are partial agonists of the RXRs.
Table 1 below discloses the results of certain assays where the compounds of the invention were tested as agonists of RAR and RXR retinoid receptors.
One such assay is a chimeric receptor transactivation assay which tests for agonist-like activity in the RARxcex1, RAPxcex2 and RARxcex3 receptor subtypes, and which is based on work published by Feigner P. L. and Holm M. (1989) Focus, 112 is described in detail in U.S. Pat. No. 5,455,265. The specification of U.S. Pat. No. 5,455,265 is hereby expressly incorporated by reference.
A holoreceptor transactivation assay and a ligand binding assay which measure the antagonist/agonist like activity of the compounds of the invention, or their ability to bind to the several retinoid receptor subtypes, respectively, are described in published PCT Application No. WO W093/11755 (particularly on pages 30-33 and 37-41) published on Jun. 24, 1993, the specification of which is also incorporated herein by reference. A detailed experimental procedure for holoreceptor transactivations has been described by Heyman et al. Cell 68, 397-406, (1992); Allegretto et al. J. Biol. Chem. 268, 26625-26633, and Mangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine, pp 319-349, Raven Press Ltd., New York, which are expressly incorporated herein by reference. The results obtained in this assay are expressed in EC50 numbers, as they are also in the chimeric receptor transactivation assay. The results of the ligand binding assay are expressed in Ki numbers. (See Cheng et al. Biochemical Pharmacology Vol. 22 pp 3099-3108, expressly incorporated herein by reference.)
Efficacy in a transactivation assay is expressed as a percentage of the maximum potency attained by the compound compared to a standard which, in this case, is the compound named (2E, 4E, 1xe2x80x2S, 2xe2x80x2S)-3-methyl-5-[2xe2x80x2-methyl-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopropyl]-penta-2, 4-dienoic acid . This standard compound is described in U.S. Pat. No. 6,114,533.
Table 1 discloses the activity of certain exemplary compounds of the invention in the above-described receptor transactivation and binding assays. Particularly, the transactivation data pertaining to activation of the RAR receptors were obtained in the chimeric assay, and the transactivation data pertaining to the activation of RXR receptors were obtained in the holoreceptor assay. In the chimeric receptor transactivation assay the compounds were essentially inactive in activating RARxcex1, RARxcex2 and RARxcex3 receptors.
In Table 1, NA stands for not active at all as an agonist and ND stands for not determined. The first row of numbers pertaining to each compound is the measured EC50 number. The second row of numbers indicates efficacy as a percentage compared to the standard compound, (2E, 4E, 1xe2x80x2S, 2xe2x80x2S)-3-methyl-5-[2xe2x80x2-methyl-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopropyl]-penta-2,4-dienoic acid. The third row of numbers pertaining to each compound is the binding Ki number.
An assay described below tests the effect of compounds of the invention on serum glucose, tryglyceride and thyroxine levels in female 9-10 weeks old db/db mice.